Circulation June 8, 2021 Issue

This week's podcast features author Nicholas Mills and Guest
Editor Allan Jaffe as they discuss the article "High-Sensitivity
Cardiac Troponin on Presentation to Rule Out Myocardial
Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial."
(https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052380)


Dr. Carolyn Lam:


Welcome to Circulation On The Run, your weekly podcast summary,
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke-National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor/Director of the Pauley
Heart Center and VCU Health in Richmond, Virginia. Well, Carolyn,
this week's feature, we're going to examine cardiac troponin,
high-sensitive cardiac troponin, and its association with
myocardial infarction. But first, before we get to that, how
about we grab a cup of coffee and start in and review some of the
other articles in the issue? Would you like to go first?


Dr. Carolyn Lam:


I would love that. The first paper brings up the problem of
stroke, remaining a devastating complication of transcatheter
aortic valve replacement or TAVR. Now, this stroke risk has
persisted despite refinements and the technique and increased
operator experience, while cerebral embolic protection devices
have been developed to mitigate this risk data regarding their
impact on stroke and other outcomes after TAVR are limited.


Dr. Carolyn Lam:


Dr. David Cohen from Cardiovascular Research Foundation in New
York and colleagues performed an observational study using data
from the STS-ACC TVT registry, including more than 123,000
patients from almost 600 sites who underwent elective or urgent
transfemoral TAVR between January 2018 and December 2019.


Dr. Greg Hundley:


Wow, Carolyn, this sounds like a really good use of the registry.
What were the results?


Dr. Carolyn Lam:


Indeed, in this nationally representative observational study,
the authors did not find an association between embolic
protection device use for TAVR and in-hospital stroke in their
primary instrumental variable analysis. And that's a technique
designed to support causal inference from observational data with
site-level preference for embolic protection device use within
the same quarter of the procedure as the instrument.


Dr. Carolyn Lam:


However, they found a modestly lower risk of in-hospital stroke
in their secondary propensity weighted analysis. These findings
provide a strong basis for large-scale randomized control trials
to really test whether embolic protection devices provide
meaningful clinical benefit for patients undergoing TAVR. And
this is discussed in a nice accompanying editorial by Dr. Tam and
with Wijeysundera from University of Toronto.


Dr. Greg Hundley:


Very nice Carolyn. Well, my first paper comes to us from
Professor Hua Zhang from Shanghai Children's Medical Center.
Cyanotic congenital heart disease is a complex pathophysiological
condition involving systemic chronic hypoxia and some cyanotic
congenital heart disease patients are chronically hypoxic
throughout their lives which heightens their risk of heart
failure as they age.


Dr. Greg Hundley:


Hypoxia activates cellular metabolic adaptation to balance energy
demands by accumulating hypoxia-inducible factor 1-Alpha. And
Carolyn, this study aims to determine the effect of chronic
hypoxia on cardiac metabolism and function in cyanotic congenital
heart disease patients and its association with age. The authors
investigated the role of hypoxia-inducible factor 1-Alpha in this
process, and the potential therapeutic targets for this were
explored.


Dr. Carolyn Lam:


What did they find Greg?


Dr. Greg Hundley:


In cyanotic congenital heart disease patients maladaptation of
cardiac metabolism occurred during puberty, along with impaired
cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout
mice, chronic hypoxia failed to initiate the switch of myocardial
substrates from fatty acids to glucose, thereby inhibiting ATP
production and impairing cardiac function. Increased insulin
resistance during puberty suppressed myocardial HIF1-Alpha and
was responsible for cardiac metabolic maladaptation in animals
exposed to chronic hypoxia.


Dr. Greg Hundley:


Pioglitazone significantly reduced myocardial insulin resistance,
restored glucose metabolism, and improved cardiac function in
pubertal chronic hypoxia animals. And so, Carolyn, perhaps future
studies could test whether pioglitazone administration during
puberty might improve cardiac function in cyanotic congenital
heart disease patients. And this article is nicely accompanied by
an editorial from Professor Ghofrani.


Dr. Carolyn Lam:


That's really interesting. For the next paper we're going from
cyanotic congenital heart disease to plain old hypertension
asking the question, What is the association of blood pressure
classification using the 2017 ACC/AHA blood pressure guideline
with risk of heart failure and atrial fibrillation? Well, this
question was addressed by Dr. Kaneko and colleagues from
University of Tokyo who performed analysis using a nationwide
health claims database collected in the JMDC claims database
between 2005 and 2018. Now note, this was more than 2 million
patients followed for a mean of more than a thousand days in whom
more than 28,000 incident heart failure, and more than 7,700
incident atrial fibrillation events occurred.


Dr. Greg Hundley:


Carolyn, this is a really large cohort a lot of events. What did
they find here?


Dr. Carolyn Lam:


Among adults not taking anti-hypertensive medications and with no
prevalent history of cardiovascular disease, stage one and stage
two hypertension, according to the 2017 ACC/AHA blood pressure
guidelines was associated with a higher incidence of heart
failure and atrial fibrillation. The population attributable
fractions for heart failure associated with stage 1 and stage 2
hypertension were 23.2% and 51.2% respectively. The population
attributable fractions for atrial fibrillation associated with
stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The
categorization based on 2017, ATC/AHA blood pressure guidelines
may improve risk stratification for identifying adults at high
risk for heart failure and atrial fibrillation.


Dr. Greg Hundley:


Wow Carolyn. Really useful data and something I love about our
journal, a transition from a large cohort study on hypertension,
and now we're going to delve into the world of preclinical
science and talk about myocardial hypertrophy. Carolyn, exercise
can induce physiological myocardial hypertrophy and former
athletes can live five to six years longer than non-athletic
control suggesting a benefit after regression of physiological
myocardial hypertrophy.


Dr. Greg Hundley:


Accordingly, these authors led by Professor Yulin Liao from
Nanfang Hospital and Southern Medical University hypothesized
that anti-hypertrophic memory exists after physiologic myocardial
hypertrophy has regressed increasing myocardial resistance to
subsequent pathological hypertrophic stress. In this study,
C57BL, six mice were submitted to 21 days of swimming training to
develop physiological myocardial hypertrophy. Then after
termination of the swimming events and exercise, the
physiological myocardial hypertrophy regressed within a week. And
these physiological myocardial hypertrophy regression mice termed
the exercise preconditioning group or HP, and then sedentary mice
as a control group underwent transverse aortic constriction, or a
sham operation and were observed for four weeks.


Dr. Greg Hundley:


Finally, in these two groups, cardiac remodeling and function
were evaluated using echocardiography invasive left ventricular
hemodynamic measurements and histological analysis.


Dr. Carolyn Lam:


Wow. Exercise induced and I hypertrophic memory in the heart.
That is so cool. Greg, could you summarize what they found?


Dr. Greg Hundley:


Yeah. And how about that exercise stimulus? The mice were
swimming. Carolyn, these authors found that exercise-induced
physiological myocardial hypertrophy can produce cardioprotective
effect. And this cardioprotective effect continues to exist after
the physiological myocardial hypertrophy subsides. And it's
termed a phenomenon exercise hypertrophy preconditioning.


Dr. Greg Hundley:


Now, mechanistically, the investigators found that exercise
hypertrophy preconditioning up regulates the expression of the
long noncoding RNA Mhrt779 by increasing the three methylation of
histone 3 at the A4 promoter of Mhrt779.


Dr. Greg Hundley:


Carolyn, also cardiac overexpression are knocked down of Mhrt779
respectively enhanced or weakened the anti hypertrophy effect of
exercise hypertrophy preconditioning. The clinical implications
of this research are that these results will likely stimulate
further research into the mechanisms of exercise hypertrophy
preconditioning, and Mhrt779 may be a potential therapeutic
target for myocardial heart hypertrophy and heart failure in
clinical practice.


Dr. Carolyn Lam:


Wow. Thanks so much, Greg. That was an incredible summary.


Dr. Carolyn Lam:


Let me tell you what else is in today's issue. There's an
exchange of letters amongst doctors Mehmood Donkor, and
Westermann regarding the article “Left Ventricular Unloading is
Associated with Lower Mortality in Cardiogenic Shock Patients
Treated with Venal Arterial Extracorporeal Membrane Oxygenation.”
There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman
with Palpitations. Is It a Poison or Is It a Reality?”


Dr. Carolyn Lam:


In Cardiology News by Tracy Hampton, she describes new research,
revealing mechanisms behind exercise-induced heart damage, new
details behind muscle injury repair, and new insights on plasma
membrane rupture during cell death. Very interesting. A new
section there. There's a Perspective piece by Dr. Passman on
“’Pill in the Pocket?’ Anticoagulation for Atrial Fibrillation.
Is That Fiction, Fact, or Foolish?”


Dr. Greg Hundley:


Great, Carolyn. Well also in the mailbag, there's a Frontiers and
medicine piece from Professor Rohatgi entitled “HDL in the 21st
Century: A Multifunctional Roadmap for Future HDL Research.” And
then finally, Carolyn, a Research Letter from Professor Felker,
entitled Probabilistic Re-adjudication of Heart Failure
Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn,
what a great group of articles summarized. How about now we
proceed to that feature discussion?


Dr. Carolyn Lam:


Let's go Greg.


Dr. Greg Hundley:


Well, listeners. We are now to our featured discussion today and
we have with us one of our associate editors who has submitted a
paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have
a guest editor. Sometimes he's been a feature author, but now
he's serving as a guest editor, Dr. Alan Jaffe from Rochester,
Minnesota. Welcome gentlemen.


Dr. Greg Hundley:


Well, Nick, could you start us off first and describe for us the
hypothesis that you wanted to test, and then maybe also provide a
little bit of context or background around the study that you and
your team have just performed.


Dr. Nicholas Mills:


Thanks, Greg. I've been working for about a decade trying to
understand how we can get the value from high-sensitivity cardiac
troponin in our clinical practice. We've tried a number of
different approaches to implement them for the benefit of patient
care that I'm particularly proud of this trial. What we'd
recognized that I think with the rollout of these assays across
Europe and more recently in America is that they're excellent
tests, but they do generate some diagnostic uncertainty in
clinical practice.


Dr. Nicholas Mills:


But as we've got used to using them, we've learned that actually
their major strength is that the confidence that they bring in
ruling out myocardial infarction rather than ruling it in. And
they allow us to make really early decisions often with a single
test at the point of arrival, where we can say with absolute
confidence that a patient does not have acute coronary syndrome
and it's unlikely to have a problem in the next 30 days or one
year based on just how low that high sense of high-sensitivity
cardiac troponin result is. And I've been a strong advocate for
using these tests in that way for some time. But the limitation
has been that much of the work in this field has been
observational. And so the patients were actually managed
accordingly because of uncertain pathways. And there's always
been some uncertainty as just how effective they are when in
clinical practice, whether using these approaches are safe. And
so we designed the Historic Trial to address that definitively in
our hospitals in Scotland.


Dr. Greg Hundley:


Very nice Nick. So what was the study population and what was the
design for this


Dr. Nicholas Mills:


Thanks Greg. So we use an interesting study design set wage
cluster, randomized controlled trial, where rather than
randomizing individual patients and randomized hospitals in
Scotland, in order to do a trial like this, you need very
detailed infrastructure because we wanted to enroll every
consecutive patient, attending our emergency departments with
symptoms, suspicions of acute cardiac syndrome. We embed it so
into our care path, which allows our clinicians to enroll
patients for us. We were keen to enroll all consecutive patients
because we wants to be confident that our findings were truly
generalizable at any included patients with complex comorbidities
presenting that of ours who were sick unwell, which is often not
the case; they've been observational studies. We randomized
hospitals and follow up patients with acute coronary syndrome up
for a year in order to determine whether the implementation of
already changed clinical care and that was safe and did not lead
to recurrent and in the future.


Dr. Greg Hundley:


Very nice. So Nick, in this randomization of hospitals, how many
total patients did you encounter and then what were your study
results?


Dr. Nicholas Mills:


So we enrolled 31,492 consecutive patients. I've crossed all
seven hospitals implementing our early relapse pathway, reduced
length of stay overall in the hospital. By just over three hours,
we increased the proportion of patients who are directly
discharged home from the emergency department by more than 50%.
So that overall 71% of patients attending hospital with possible
acute coronary syndrome were able to be discharged from the
emergency department rather than being admitted unnecessarily for
further investigations. But the critical result was, was that
major change in the care pathway safe. We had a non-inferiority
design. We had a very small number of safety outcomes at 30 days,
and it was difficult to prove non-inferiority, but the event rate
favored the implementation there.


Dr. Nicholas Mills:


They will have pathway with the 0.4% of patients we attend within
30 days of heart attack or dying from heart disease for our
implementing it and 0.3% in and crucially, we followed everyone
up for a year and were able to demonstrate that the safety
outcome was not increased in those that we are able to that
pathway one year with absolute confidence. And furthermore, there
was no difference in re attendance or an all-cause mortality. We
the two different arms of the trial. So we concluded that the
early relapse pathway was effective and safe, and that using this
approach we'd have major benefits from patients who can avoid
unnecessary for healthcare providers in terms of reducing actual
cost limitations.


Dr. Greg Hundley:


Fantastic. Well listeners, we're now going to turn to our guest
editor, Dr. Alan Jaffe, and Alan, could you help us put into
perspective these new data regarding high sensitivity, proponent,
and also comment what attracted you to this article so much so
that you feel it's needs to be published and circulated worldwide
in the literature?


Dr. Allan Jaffe:


One of the important areas in the field of biomarkers is the
movement just finally occurring. And Nick has been the forefront
of this, of starting to do randomized trials. Observational data
is just that it's observational. The patients are not created
based on the information that is by the biomarkers. Patients can
be missed if you're missing a sample, you exclude those patients.
In addition, most observational trials, try and get informed
consent. And by getting informed consent often miss the sickest
patients. So what's desperately needed by the field. And which is
just now starting with two or three ongoing randomized trials is
just that a randomized trial where the investigators are forced
to use the data, to manage the patient. And by using the step
wedge design that Nick and his group has used in other trials as
well, they guarantee that they don't miss patients either.


Dr. Allan Jaffe:


So that it's comprehensive and takes all into account. This is
terribly important to then validate things like in this instance,
the rule-out pathway. And I think these data do substantially
confirm the fact that a single sample rule-out strategy using the
cutoff value that Nick had previously established as optimizing
the percentage of the population that can be included works well.
It is unfortunate that the way in which they design their trial
mist and design their non-inferiority outcome for safety was such
that they ended up not finding significance to that. But I agree
with Dr. Mills in the sense that the outcome adverse effects were
so low, that despite that I think there's very important and
reasonable data that this strategy is also safe.


Dr. Greg Hundley:


Very good. Well, Nick, thinking forward, what do you feel is the
next study that needs to really be performed in this area?


Dr. Nicholas Mills:


I completely agree with everything Alan said. I think there's
lots of really interesting approaches to find a group diagnosis,
risk stratification of this really common condition. We need
trials that demonstrate these approaches actually influence care
and outcomes. For me, the challenge remains how to really harness
these great tests to route the ruler of my cognitive function. I
run about ads of patients with elevated cardiac troponin added
due to an underlying condition that is an acute coronary
syndrome. And we're starting to think about ways in which we can
individualize our decision-making a little bit moving to walk
away from binary thresholds, because values are influenced by
age, by sex, by comorbidities like renal disease and preexisting
heart failure about heart disease.


Dr. Nicholas Mills:


And by incorporating some of these patient factors into the
interpretation of cardiac troponin. I think we can give
clinicians better guidance on who to treat early with
antiplatelet therapies and who needs invasive investigation than
just simply saying that the troponin concentration is all
positive or negative. And it's our challenge, I think, is how to
harness that information, make it workable in clinical practice,
and then demonstrate that by doing so we actually target
effective therapies better, and that it makes a difference for
patient care. So this is where we're working on at the moment.
And I hope that in due course, we'll be able to do randomized
trials in this space and that will move things forward again.


Dr. Greg Hundley:


Alan, do you have anything you'd like to add to that?


Dr. Allan Jaffe:


Yes. I think we're in a new era. We are finally starting to see
there are now two or three randomized trials. It is time that the
biomarker diagnostic studies graduate to a higher level of
evidence, meaning randomized controlled trials. Nick is leading
the way in that regard and I suspect and hope that subsequent
trials, although observational trials may help inform which ones
we should do, but that subsequent trials will continue to be
randomized and generate the more robust data that randomized
trials are capable of generating.


Dr. Greg Hundley:


Well, thank you both. And Nick, thank you for bringing us this
research and also Alan, for evaluating it and providing this
commentary today. It's quite exciting to have really this new
information produced from a randomized trial, which evaluated the
utility of a low high sensitivity treponema value in patients
presenting to hospitals with chest pain syndromes. Well, on
behalf of Carolyn and myself, we want to wish you a great week
and we will catch you next week on the run. This program is
copyright of the American Heart Association 2021. The opinions
expressed by speakers in this podcast are their own and not
necessarily those of the editors or of the American Heart
Association for more visit ahajournals.org.